Original Article

Cardiac Neurosis: Exercise Tolerance and the Role

of Sympathetic Activity
Hiroyuki MlYAKODA, Hideyuki KlTAMURA, Toru KlNUGAWA,
Makoto SAITO, Hiroshi KOTAKEand Hiroto MASHIBA

To evaluate the cardiovascular and plasma catecholamine responses to dynamic exercise in patients with
cardiac neurosis (CN), treadmill testing was performed. Thirty-four patients with CNwere chosen for this
study based on exercise tolerance and the results were compared with those in 31 patients with organic heart
disease and 12 normal subjects. Patients with CNshowed an augmentation of cardiovascular and plasma
catecholamine responses. The augmentation of the norepinephrine response in patients with CNwas not as
remarkable as that in patients with organic heart disease. Onthe other hand, the augmentation of the epinephrine
response was greater in patients with CNthan in those with organic heart disease. Administration of metoprolol
(40 mg/day) for two weeks improved exercise tolerance in patients with CN.Wesuggest that anxiety augments
both sympatho-neural and sympatho-adrenal activity and that it is the symptoms induced by the augmented
cardiovascular response which reduce exercise tolerance in patients with CN.
Key words: Irritable heart syndrome, Hyperkinetic heart syndrome, Neurocirculatory asthenia,
Treadmill exercise testing, Plasma catecholamine concentrations, Beta blocker

Cardiac neurosis (CN) is a psychophysiological whether or not the characteristic response of plasma
syndrome characterized by cardiovascular and catecholamines to dynamic exercise occurs in
nervous symptoms in the absence of underlying patients with CN. Therefore, the cardiovascular and
organic disorders. This syndrome is regarded to be plasma catecholamine responses during treadmill
similar to irritable heart syndrome (1), soldier's exercise testing were evaluated in patients with CN
heart, effort syndrome, hyperkinetic heart syndrome and the results were compared with those in patients
(2), hyperdynamic beta-adrenergic circulatory state with organic heart disease and in normal subjects.
(3), and neurocirculatory asthenia. Dyspnea, palpita- Additionally, the effects of blockade of beta-
tion and nervousnessare commonsymptomsboth adrenergic receptors on exercise tolerance was
at rest and during effort. This condition is assumed evaluated.
to be a hyperkinetic cardiovascular state based on METHODS
anxiety. Sympathetic activity has an important role
in cardiovascular response to a variety of stress Su bjects
types. Previous studies (4-6) showed an increase in Westudied 34 patients (ll men, 23 women; mean
plasma catecholamine concentrations in patients age 48 ± 13 years) with symptoms characteristic of
with panic and anxiety disorders. However, few CN(dyspnea, palpitation, nervousness and anxious-
reports have been published on the plasma cate- ness), 31 patients (ll men, 20 women; mean age
cholamine response to dynamic exercise in patients 53± 10 years) with organic heart disease, and 12
with CNand in these reports the results do not agree normal subjects (8 men, 4 women; mean age 42± 14
years).
(7-9). The purpose of this study was to investigate
From the First Department of Internal Medicine, Tottori University School of Medicine, Yonago
Received for publication March 22, 1990; Accepted for publication July 24, 1990
Reprint requests should be addressed to Hiroyuki Miyakoda, MD,The First Department of Internal Medicine,
Tottori University School of Medicine, 36-1 Nishimachi, Yonago 683, Japan
Jpn J Med Vol 29, No 5 (September, October 1990) 493
 Miyakoda et al

The diagnosis of CN was made based on physical the exercise time from 8 to 10 min, whenexercise
and laboratory examinations (chest roentgeno- tolerance was a work load of the third exercise stage.
graphy, electrocardiography, 24-h ambulatory And good tolerance was defined as the exercise time
electrocardiographs recording, echocardiography, of ll minor more, whenexercise tolerance wasa
spirography, etc.) and explanatory cardiovascular, work load of the fourth exercise stage or more.
respiratory, and endocrine diseases were excluded. Measurement of plasma catecholamine concentra-
The 31 patients with organic heart disease con- tions
sisted of 4 patients with old myocardial infarction Blood samples were kept in ice water. After
without angina pectoris, 1 patient with dilated centrifugation, plasma samples were kept frozen at
cardiomyopathy, 8 patients with aortic valvular -40°C. Plasma norepinephrine and epinephrine
disease, 14 patients with mitral valvular disease, and concentrations were measured by the THI (tri-
4hadpatients with atrial septal
atrial fibrillation.
defect. Twelve patients
Fourteen patients were re-
hydroxyindole) method with a high-performance
liquidchromatograph.
ceiving long-term digitalis and diuretic therapy, and Evaluation of effects of metoprolol
9 patients were receiving long-term vasodilator Effects of metoprolol on exercise tolerance and
therapy. Vasodilators were withdrawn for 48 h prior cardiovascular responseto exercise wereevaluated
to exercise testing. in 8 patients with CN. After consent was obtained,
Treadmill exercise testing the daily dosage of metoprolol, 40 mg, was ad-
A 19-gauge indwelling catheter was placed in the ministered in two portions. The concomitant use of
antecubital vein of the right arm and a small amount anti-anxiety drugs was avoided. Twoweeksafter ad-
of physiological saline was continuously infused. ministration, treadmill exercise testing was repeated.
Subjects remained in the supine position for 15 min. Exercise after administration was terminated by the
Blood (3 ml) was drawn for the measurement of appearance of a symptomequivalent to that in the
plasma catecholamine concentration. Blood pressure test before administration.
was measured with an automatic sphygmoma- Statistical analysis
nometer (Nippon Colin, STBP-680) on the left Data are represented as mean± SDin the text and
arm. Multistage treadmill exercise testing was mean±SEMin the figures. Data were analyzed
performed on a computerized system (Marquette, using the t-test. p values of less than 0.05 were con-
CASE2) according to the modified Bruce protocol sidered significant.
(10) in which the load level was increased every 3 RESULTS
min and a stage of 3.8 mphand 14%was added.
Electrocardiogram recording and measurement of Exercise tolerance (Table 1)
blood pressure were performed every min during Of 34 patients with CN, 13 had poor tolerance,
exercise. End points were defined as the occurrence 10 had fair tolerance, and ll had good tolerance.
of moderate dyspnea or palpitation in patients and Of 31 patients with organic heart disease, 20 had
the achievement of 85%of age-predicted maximal poor tolerance, and ll had fair tolerance. All 12
heart rate in normal subjects. Blood samples were normal subjects had good tolerance. Then heart rate,
obtained during the last min of each exercise stage systolic blood pressure, plasma norepinephrine and
in normal subjects and immediately after exercise epinephrine concentrations at rest and at the peak
in all patients and normal subjects. Patients without exercise in both patient groups with poor tolerance
moderate symptomon achievement of 85%of age- were compared with those at rest and at the end of
predicted maximalheart rate were excluded. the second exercise stage in normal subjects,
Evaluation of exercise tolerance respectively. The results at rest and at the peak
Exercise time in treadmill testing was regarded exercise in both patient groups with fair tolerance
as the index of exercise tolerance. Poor tolerance was were comparedwith those at rest and at the end of
defined as the exercise time from 3 to 7 min, when the third exercise stage in normal subjects,
exercise tolerance was a work load of the first or respectively. Andthe results at rest and at the peak
second exercise stage. Fair tolerance was defined as exercise in the CNpatient group with good tolerance
494 Jpn J Med Vol 29, No 5 (September, October 1990)
Sympathetic Activity and Cardiac Neurosis
Table 1. Patient groupingbased on exercise tolerance.

Cardiac neurosis

Organic heart disease

13

20

Normal
ExerciseFair
Poor

ET
n
4.8±1.4*
tolerance

ET
1
9.4±1.0

5.1±1.4ll
0 n

9.0±0.9n
ll

12
Good

ET
13.9±1.3

143±0.9

n, number of patients; ET, exercise time (min)

*Values are mean± SD.

were comparedwith those at rest and at the peak significant difference in HRat the peak exercise
exercise in normal subjects, respectively. between the good tolerance CNgroup (147± 15
beats/min) and normal subjects (148± 15 beats/
Heart rate (Fig. 1) min).
Heart rate (HR) at rest was significantly higher
in the poor tolerance CNgroup than in normal Systolic blood pressure (Fig. 2)
subjects. HRat the peak exercise in both patient The systolic blood pressure (SBP) of patients with
groups with poor tolerance (CN, 140 ± 16; organic CNand that of normal subjects was comparedas
heart disease, 134 ± 19 beats/min) was significantly the SBP response is influenced by organic heart
higher than that at the end of the second exercise disease. SBPat rest and at the peak exercise in the
stage in normal subjects (102± 13 beats/min). HR poor tolerance CN group (exercise, 167 ± 25 mmHg)
at the peak exercise in both patient groups with fair was significantly higher than that at rest and at the
tolerance (CN, 145± 13; organic heart disease, end of the second exercise stage in normal subjects
135 ±20 beats/min) was significantly higher than (exercise, 134± 17 mmHg), respectively. SBP at the
that at the end of the third exercise stage in normal peak exercise in the fair tolerance CN group
subjects (118± ll beats/min)0 And there was no (170± 35 mmHg)tended to be higher than that at
the end of the third exercise stage in normal subjects
à" CNPOOR à" CNFAIR à" CNGOOD (145 ± 17 mmHg) (p <0.1). And there was no signif-
bpm *HPOOR *HFAIR
2001 B NSTAGE2 200-1 " nSTAGE3 200-, B WPEAK icant difference in SBPat the peak exercise between
Ol mmHg à" CNPOOR à" CNFAIR à" CNGOOD
jS 150- fá"1 150- x^ 150- x I D 200 *NSTAGE2 200 bNSTAGE3 20O-, BHPEAK
V>
V>

t loo- //y^ 10°" /A/ 10° // S

a t" 1 I T
3 150- ^/ 150 / t 150- //
50- i j 50- 50-

OJ

REST EX
<H

REST EX
0-

REST EX
i
CO
f^
*
/
*
/
W) 100J ^ 100 100
Fig. 1. Heart rate (HR) response to multistage tread- REST EX REST EX REST EX

mill exercise in patients with cardiac neurosis (CN), those Fig. 2. Systolic blood pressure (SBP) response to
with organic heart disease (H), and normal subjects (N).
Patients were grouped based on exercise tolerance (poor, fair multistage treadmill exercise in patients with cardiac neurosis
or good). HRat the peak exercise in patient groups was (CN) and normal subjects (N). Patients were grouped based
comparedwith that at the equivalent level of exercise (at the on exercise tolerance. SBP at the peak exercise in patient
end of the second or third exercise stage or at the peak groups was compared with that at the equivalent level of
exercise) in normal subjects. *p<0.05. exercise in normal subjects. *p<0.05.
495
Jpn J Med Vol 29, No 5 (September, October 1990)
 Miyakoda et al

the good tolerance CN group (171 ± 16 mmHg) and fair tolerance organic heart disease group
normal subjects (162± 14 mmHg). (1 135 ± 517 pg/ml) was significantly higher than that
at the equivalent level of exercise in the fair tolerance
Plasma norepinephrine concentration (Fig. 3) CN group and in normal subjects. And plasma NE
There was no significant difference in plasma concentration at the peak exercise wassignificantly
norepinephrine (NE) concentration at rest between higher in the good tolerance CN group (724± 321
the poor tolerance CNgroup (152 ± 52 pg/ml) and pg/ml) than in normal subjects (461 ± 169 pg/ml),
normal subjects (123 ± 37 pg/ml). Plasma NE con- while there was no significant difference in plasma
centration at rest was significantly higher in the poor NEconcentration
(CN, 130±28
at rest between these two groups
pg/ml).
tolerance organic heart disease group (223 ± 115
pg/ml) than in either the poor tolerance CNgroup
or normal subjects. Plasma NEconcentration at the Plasma epinephrine concentration (Fig. 4)
peak exercise in both patient groups with poor Plasma epinephrine (E) concentration at rest was
tolerance (CN, 675 ±357; organic heart disease, significantly higher in the poor tolerance CNgroup
954 ± 488 pg/ml) was significantly higher than that (45±36 pg/ml) than in normal subjects (22± ll
at the end of the second exercise stage in normal pg/ml). Plasma E concentration at rest in the poor
subjects (265 ± 79 pg/ml). There was no significant tolerance organic heart disease group (25 ± 24 pg/ml)
difference in plasma NEconcentration at the peak was not significantly different from that at rest in
exercise between both patient groups with poor the poor tolerance CNgroup or in normal subjects.
tolerance. There were no significant differences in Plasma E concentration at the peak exercise in the
plasma NEconcentration at rest amongpatient poor tolerance CN group (108±66 pg/ml) was
groups with fair tolerance (CN, 146± 51; organic significantly higher than that at the peak exercise in
heart disease, 180 ± 85 pg/ml) and normal subjects. the poor tolerance organic heart disease group
Plasma NEconcentration at the peak exercise in the (48 ± 25 pg/ml) and at the end of the second exercise
fair tolerance CN group (676±279 pg/ml) was stage in normal subjects (28 ± 19 pg/ml). Plasma E
significantly higher than that at the end of the third concentration at the peak exercise in the poor
exercise stage in normal subjects (305 ± 90 pg/ml). tolerance organic heart disease group was not
Plasma NEconcentration at the peak exercise in the significantly different from that at the end of the
à" CNPOOR à" CNFAIR à" CNGOOD
pg/ml a HPOOR * H FAIR à" CN POOR à" CN FAIR à" CN GOOD
1500 "NSTAGE2 1500 å NSTAGE3 1500 å NPEAK * HPOOR * HFAIR
pg/ml . NSTAGE2 . NSTAGE3 å NPEAK
140 r-i-, 140 140-,
n
* . T
UJ 120- 120 120-

il
m iooo- I 7 i
4
iooo- /I

/
1000-

^
I
UJ
f
100

80- /
/A
/ 100

80- T
100-

80-

| 60- / 60- /i
/ /IT 60-
I
/JT
S 500- // 500- // 500- / t
3 40-1^^ 40- ///^ 4°- //
a / à" / ^4 / / 20- K- ~~* 20- {& 20- //

L__t
0J à"à"uu 0J 0J oJ 0-" o-
REST EX REST EX REST EX REST EX REST EX REST EX

Fig. 3. Plasma norepinephrine (NE) response to Fig. 4. Plasma epinephrine (E) response to multistage
multistage treadmill exercise in patients with cardiac neurosis treadmill exercise in patients with cardiac neurosis (CN), those
(CN), those with organic heart disease (H), and normal with organic heart disease (H), and normal subjects (N).
subjects (N). Patients were grouped based on exercise
Patients were grouped based on exercise tolerance. Plasma
tolerance. Plasma NE concentration at the peak exercise in E concentration at the peak exercise in patient groups was
patient groups was comparedwith that at the equivalent level compared with that at the equivalent level of exercise in
of exercise in normal subjects. *p <0.05. normal subjects. *p<0.05.

496
Jpn J Med Vol 29, No 5 (September, October 1990)
Sympathetic Activity and Cardiac Neurosis

second exercise stage in normal subjects. There were in A NE between the patient groups with poor
tolerance (CN, 522±324; organic heart disease,
no significant differences in plasma E concentration 724±447 pg/ml). A NE in both patient groups with
poor tolerance was significantly higher than that at
at rest among patient groups with fair tolerance (CN, the end of the second exercise stage in normal
subjects (143±53 pg/ml). A NE in the fair
19± 12; organic heart disease, 20± 10 pg/ml) and tolerance CN group (537±236 pg/ml) was signif-
icantly higher than that at the end of the third
normal subjects. Plasma E concentration at the peak exercise stage in normal subjects (188 ± 71 pg/ml).
A NE in the fair tolerance organic heart disease
exercise in the fair tolerance CN group (75±44 group (955 ±479 pg/ml) was significantly higher
pg/ml) tended to be higher than that at the end of than
at thethatendinofthethefairthirdtolerance
exercise CNgroup
stage in and that
normal
the third exercise stage in normal subjects (44 ± 23 subjects.
(594 ± 329 A NE inwasthenotgood
pg/ml) tolerance different
significantly CNgroup
pg/ml) (p <0.1). Plasma E concentration at the peak from
(378 that
± 150 atpg/ml).
the peak exercise in normal subjects
exercise in the fair tolerance organic heart disease Changes
6) in plasma epinephrine concentration (Fig.
group (59 ± 46 pg/ml) was not significantly different The change in plasma E concentration ( A E) was
from that at the peak exercise in the fair tolerance measured inthe CN
poor tolerance samemanner as A NE.
group (64±52 A Einthe
pg/ml) was
CNgroup and at the end of the third exercise stage significantly
organic heartof higher
disease than
groupthat
(25 in± the poor tolerance
19 stage
pg/ml)
in normal subjects. There was no significant at the end the second exercise inandnormal
that
subjects
organic (7 ± disease
13 pg/ml). A Ewasin significantly
the poor tolerance
difference in plasma E concentration either at rest than thatheart
at the end ofgroup
the second exercise stage higherin
or at the peak exercise between the good tolerance normal subjects. There was no significant
in A E between the patient groups with fair difference
CNgroup (rest, 22± 12; exercise, 65 ± 33 pg/ml) and
normal subjects (exercise, 53 ± 24 pg/ml).
Changes in plasma norepinephrine concentration
(Fig. 5)
The change in plasma NE concentration ( A NE)
was measured by comparing plasma NEconcentra-
tion at rest with the value at the peak exercise in
patients with CN and those with organic heart
disease, and by comparing plasma NE concentra-
tion at rest with the value at the end of the second
or third exercise stage, or at the peak exercise in
normal subjects. There was no significant difference

1 !
CN H N CN H N
CNFAIRSTAGE3
H N CNGOOD
N PEAK
POOR STAGE 2 CN H N CN N
FAIR STAGE3 GOOD PEAK POOR STAGE2

Fig. 5. Changes in plasma norepinephrine concentration Fig. 6. Changes in plasma epinephrine concentration
( 4 NE) during multistage treadmill exercise in patients with ( A E) during multistage treadmill exercise in patients with
cardiac neurosis (CN), those with organic heart disease (H), cardiac neurosis (CN), those with organic heart disease (H),
and normal subjects (N). Patients were grouped based on and normal subjects (N). Patients were grouped based on
exercise tolerance. A NEin patient groups was compared exercise tolerance. A E in patient groups was compared with
with that at the equivalent level of exercise stage in normal that
*p<0.05.
at the equivalent level of exercise in normalsubjects.
subjects. *p <0.05.
497
Jpn J Med Vol 29, No 5 (September, October 1990)
 Miyakoda et al

tolerance (CN, 55 ± 38; organic heart disease, 44 ± 39 DISCUSSION

pg/ml); J E in these two groups was significantly
higher than that at the end of the third exercise stage In recent years the psychophysiological syndrome
in normal subjects (21 ±21 pg/ml). A E in the good represented by CNhas been considered to be a
tolerance CN group (43±31 pg/ml) was not clinical entity based on anxiety. CN is characterized
significantly different from that at the peak exercise by symptomssuggesting sympathetic hyperactivity.
in normal subjects (42± 31 pg/ml). Plasmacatecholamineconcentrations are considered
to be an index of sympathetic activity. Generally,
Effects of metoprolol (Fig. 7) emotional stress induces mainly an increase in
After administration of metoprolol, the exercise epinephrine from adrenal medullae. On the other
time was significantly prolonged (from 7.5 ± 4.6 to hand, dynamic exercise stress induces primarily an
10.8 ± 3.4 min). HR at rest significantly decreased increase in norepinephrine from postganglionic
from 77+ ll to 62±9 beats/min. HR both at the sympathetic nerves. Several reports showed an in-
time equal to the peak exercise time before ad- crease in plasma norepinephrine and/or epinephrine
ministration (102± 12 beats/min) and at the peak concentrations at rest in patients with anxiety
exercise (124 ± 16 beats/min) was significantly lower disorders (4-6). However, only a few reports on
than the value at the peak exercise before administra- the relation between the reduction of workcapacity
tion (145 ± 13 beats/min). SBP at rest remained un- and the response of sympathetic activity to dynamic
changed (135±18 vs 130±30 mmHg). SBP at the exercise stress in patients with CM have been
time equal to the peak exercise time before ad- published and the published results are not in agree-
ministration (156± 16 mmHg)was significantly ment (7-9). And there is no report on the com-
lower than the value at the peak exercise before ad- parison of the response of sympathetic activity to
ministration (183±31 mmHg). SBP at the peak exercise between patients with CNand those with
exercise tended to decrease (from 183±31 to organic heart disease. Francis et al (1 1) reported that
174±29 mmHg, p<0.1). No obvious side effects the plasma norepinephrine concentration is elevated
were observed. at rest and is more markedly increased at lower levels
EXERCISE SYSTOLIC of dynamic exercise in patients with congestive heart
TIME HA1 E BLOOD PRESSURE failure than in normal subjects. This increase is
min , à" ,
bpm
200-,
mmHg
200-. rn
attributed to the reflex stimulation of the sym-
12-1 T * T
pathetic nervous system which maysupport cardiac
function. On the other hand, the plasma epinephrine
9-T
y
>/
100-
/
/yr
^s%.
150- /
/
yi
\S
concentration was similar between these two groups
at rest, and showed changes during dynamic exercise
50- ^ j
somewhat similar to those of plasma norepinephrine
concentration. However the difference between these
3-" i i 0-* i i i 100J i , , two groups at lower levels of dynamic exercise was
BEFORE AFTER REST PEAK
BEFORE
PEAK
AFTER
REST PEAK
BEFORE
PEAK
AFTER
not as remarkable as plasmanorepinephrine con-
centration. This finding indicates that adrenal
Fig. 7. Exercise time, heart rate (HR), and systolic blood medullae are not major sources of plasma cate-
pressure (SBP) during multistage treadmill exercise before cholamines during dynamic exercise. The progres-
and after two weeks of administration of metoprolol (40 sion of anaerobic metabolism in peripheral organs
mg/day) in 8 patients with cardiac neurosis. à" , values before during exercise is assumed to be a stimulus in the
administration; O , values after administration. HRand SBP
both at the time equal to the peak exercise time before ad- activation of the sympathetic nervous system (12).
ministration and at the peak exercise after administration were In this study we confirmed the reduction of
comparedwith the value at the peak exercise before ad- exercise tolerance in patients with CN. Then we
ministration. *p <0.05. divided patients with CNand those with organic
heart disease into groups based on exercise tolerance,
and compared the cardiovascular and plasma
498
Jpn J Med Vol 29, No 5 (September, October 1990)
Sympathetic Activity and Cardiac Neurosis

Assoc 182: 823, 1962.

catecholamineresponses to exercise amongpatient
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1966.
circulatory state. Arch Intern Med 117: 614,
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5) Nesse RM, Cameron OG, Curtis GC, McCann DS,
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